PD1+ tumor associated macrophages predict poor prognosis of locally advanced esophageal squamous cell carcinoma.

Aim: Tumor associated macrophages are the most abundant cancer immune cells. However, little was known about the identity of CD68+PD1+ macrophages as well as the contributions in the prognosis of esophageal squamous cell carcinoma (ESCC). Methods & methods: Immunofluorescence, flowcytometry and RT-PCR were used to analysis PD1+ macrophages in ESCC. Results: CD68+PD1+ macrophages which can express higher M2 markers in cancer tissues, increased about 4.2-times compared with para-cancer tissues. Additionally, PD1high macrophages were significantly correlated with more malignant phenotypes and poor prognosis. PD1 treatment can enhance phagocytosis of cultured macrophages and redirect this macrophage to M1-like phenotype. Conclusion: Thus, our findings overall indicate that CD68+PD1+ macrophages are tumor associated macrophagess in ESCC, which can forecast the prognosis of ESCC.

Transcription factor STAT4 counteracts radiotherapy resistance in breast carcinoma cells by activating the MALAT1/miR-21-5p/THRB regulatory network.

Considering the limited research and the prevailing evidence of STAT4's tumor-suppressing role in breast carcinoma (BC) or in breast radiotherapy (RT) sensitivity requires more in-depth exploration. Our study delves into how STAT4, a transcription factor, affects BC cell resistance to radiotherapy by regulating the MALAT1/miR-21-5p/THRB axis. Bioinformatics analysis was performed to predict the regulatory mechanisms associated with STAT4 in BC. Subsequently, we identified the expression profiles of STAT4, MALAT1, miR-21-5p, and THRB in various tissues and cell lines, exploring their interactions and impact on RT resistance in BC cells. Moreover, animal models were established with X-ray irradiation for further validation. We discovered that STAT4, which is found to be minimally expressed in breast carcinoma (BC) tissues and cell lines, has been associated with a poorer prognosis. In vitro cellular assays indicated that STAT4 could mitigate radiotherapy resistance in BC cells by transcriptional activation of MALAT1. Additionally, MALAT1 up-regulated THRB expression by adsorbing miR-21-5p. As demonstrated in vitro and in vivo, overexpressing STAT4 inhibited miR-21-5p and enhanced THRB levels through transcriptional activation of MALAT1, which ultimately contributes to the reversal of radiotherapy resistance in BC cells and the suppression of tumor formation in nude mice. Collectively, STAT4 could inhibit miR-21-5p and up-regulate THRB expression through transcriptional activation of MALAT1, thereby mitigating BC cell resistance to radiotherapy and ultimately preventing BC development and progression.

Anti-PD-L1 Antibody Enhances T Cell Immune Responses and Reduces Resistance of Breast Cancer Cells to Radiotherapy.

Immune escape is a frequent occurrence, which limits the duration of antitumor immune responses to radiotherapy. Here, we aimed to ascertain the roles and underlying mechanisms of programmed death ligand 1 (PD-L1) in tolerance of breast cancer (BC) to radiotherapy. We first quantified microRNA-21 (miR-21) and PD-L1 expression in BC tissues and cells, followed by identification of the interactions between miR-21, PD-L1, and programmed cell death protein 4 (PDCD4). miR-21 knock-in mice were used to construct tumor-bearing models, which were then treated with anti-PD-L1 antibody and irradiation, followed by measurement of tumor growth and tumor immune escape. Finally, we evaluated the synergistic effects of radiotherapy and anti-PD-L1 antibody in vivo. The results showed increased miR-21 expression in BC tissues and cells, which was positively correlated with PD-L1 expression. The treatment with radiotherapy or anti-PD-L1 antibody in the miR-21 knock-in mice diminished tumor weight and volume, along with decreased CD3+CD8+ positive cells, serum IL-2 and IFN-γ levels, and lower PD-L1 expression, but augmented apoptosis of T and BC cells. Moreover, miR-21 significantly augmented PD-L1 expression via PI3K/Akt pathway activation by targeting PDCD4 in BC cells. Thus, radiotherapy and anti-PD-L1 antibody synergistically accelerated the therapeutic effect against BC in mice, thereby implicating a close interplay between radiotherapy, T cells, and the miR-21/PDCD4/PI3K/Akt/PD-L1 axis.

Field-tuned quantum effects in a triangular-lattice Ising magnet.

We report thermodynamic and neutron scattering measurements of the triangular-lattice quantum Ising magnet TmMgGaO4 in longitudinal magnetic fields. Our experiments reveal a quasi-plateau state induced by quantum fluctuations. This state exhibits an unconventional non-monotonic field and temperature dependence of the magnetic order and excitation gap. In the high field regime where the quantum fluctuations are largely suppressed, we observed a disordered state with coherent magnon-like excitations despite the suppression of the spin excitation intensity. Through detailed semi-classical calculations, we are able to understand these behaviors quantitatively from the subtle competition between quantum fluctuations and frustrated Ising interactions.

Trends in the Use of Sphingosine 1 Phosphate in Age-Related Diseases: A Scientometric Research Study (1992-2020).

OBJECTIVES: This study was designed to explore the intellectual landscape of research into the application of sphingosine 1 phosphate (S1P) in age-related diseases and to identify thematic development trends and research frontiers in this area. METHODS: Scientometric research was conducted by analyzing bibliographic records retrieved from the Web of Science (WOS) Sci-Expanded Database dated between 1900 and 2020. Countries, institutions, authors, keyword occurrence analysis, and cooperation network analysis were performed using the CiteSpace and VOSviewer software. RESULTS: A total of 348 valid records were included in the final dataset, and the number of publications and the frequency of citations have grown rapidly over the last ten years. The USA (n = 175), China (n = 42), and Germany (n = 37) were the three largest contributors to the global publications on S1P and aging, while the Medical University of South Carolina (n = 15), University of California, San Francisco (n = 13), and University of Toronto (n = 13) were the leading institutions in this field. Analysis showed that early studies primarily focused on the mechanism of S1P intervention in AD. While S1P and its relevant metabolites have remained a long-term active area of research, recent studies have focused more on interventions aimed at improving retinal degeneration, cardiomyopathy, multiple sclerosis, and diabetes, among others. CONCLUSIONS: It is worth mentioning that this manuscript is the first to describe any bibliometric analysis of S1P and its application in age-related interventions. This study includes a discussion of the (1) historical overview of the topic; (2) main contributors: journals, countries, institutes, funding agencies, and authors; (3) collaboration between institutes and authors; (4) research hot spots and zones; and 5) research trends and frontiers. This will enable scholars to understand the current status of S1P research in age-related diseases.

Prognostic biological factors of radiation pneumonitis after stereotactic body radiation therapy combined with pulmonary perfusion imaging.

Radiation pneumonitis (RP) is one of the most common dose-limiting toxicity syndromes in patients with thoracic malignant tumors receiving radiotherapy. The present study aimed to identify biological factors for the prediction of RP. Pulmonary perfusion imaging is capable of reflecting the differential functional activity of various regions of the lung, and in the present study, radiotherapy plans that were established on the basis that pulmonary perfusion images have high biological conformality, which may identify regions vulnerable to RP to spare them from radiation. A total of 46 patients with non-small cell lung cancer (NSCLC), exhibiting high and low levels of apurinic/apyrimidinic endonuclease-1 (Ape-1), intercellular adhesion molecule (ICAM)-1 and interleukin (IL)-17A prior to treatment, with SBRT with respective cut-off values of 4.2, 3.0 and 5.1 µg/l were stratified into groups A and B. Patients received radiation doses within the margin of the planning target volume. Stereotactic body radiation therapy (SBRT) was used for the treatment of NSCLC and single-photon emission computed tomography pulmonary perfusion imaging was used to assess all patients for the presence of RP. Furthermore, the serum levels of Ape-1, ICAM-1 and IL-17A were examined by ELISA. Prior to SBRT, perfusion images indicated that no RP was present in any of the patients, and 23 patients had high levels of Ape-1, ICAM-1 and IL-17A. After SBRT, 22 out of 23 patients in group A (95.65%) presented with RP and 1 patient (4.35%) had no RP. In group B, 6 out of 23 patients (26.09%) had RP and 17 patients (73.91%) had no RP after SBRT. The difference between the two groups in the incidence of RP was significant (P=1.66×10-12 <0.05). In conclusion, high levels of Ape-1, ICAM-1 and IL-17A are associated with an increased risk of RP. A further analysis should be performed in the future to verify whether these factors have significant prognostic value.

[Correlations between Ape1/Ref-1, ICAM-1 and IL-17A Levels in Serum and Radiation Pneumonitis for Local Advanced Non-small Cell Lung Cancer Patients].

BACKGROUND: The main manifestations of radiation pneumonitis are injury of alveolar epithelial and endothelial cells, abnormal expression of cytokines, abnormal proliferation of fibroblasts and synthesis of fibrous matrix. The occurrence of radiation pneumonitis is associated with multiplecytokine level abnormality. These cytokines can also be used as bio-markers to predict the occurrence of radiation pneumonitis. This study was to evaluate the correlation between the change of apurinic/apyrimidinic endonuclease 1/redox factor-1 (Ape1/Ref-1), intercellular adhesion molecules 1 (ICAM-1) and interleukin-17A (IL-17A) before and after radiotherapy and radiation pneumonitis for local advanced non-small cell lung cancer (NSCLC) patients with concurrent chemoradiotherapy. METHODS: NSCLC patients (68 cases) were treated with concurrent radiotherapy and chemotherapy, every patient's normal tissue were controlled with a same radation dose. 68 local advanced NSCLC patients with concurrent chemoradiotherapy were detected the levels of Ape1/Ref-1, ICAM-1 and IL-17A in serum by ELISA before radiotherapy and in the 14th week after radiotherapy. Acute and advanced radiation pulmonary injury was graded according to Radiation Therapy Oncology Group/European Organization For Research and Treatment (RTOG/EORTC) diagnostic and grading criteria. Grade 2 or more radiation pneumonitis was taken as the main end point. RESULTS: Eighteen cases out of 68 developed radiation pneumonitis, 50 of 68 cases have no radiation pneumonia development. There was no significant change of Ape1/Ref-1 levels before and after radiotherapy in radiation pneumonitis group (P>0.05). There was no significant change of Ape1/Ref-1 concentration in serum after radiotherapy between radiation pneumonitis group and non-radiation pneumonitis group (P>0.05). Compared with before radiotherapy, upregulation degree of ICAM-1 levels in radiation pneumonitis group was significantly higher than that in non- radiation pneumonitis group (P<0.05). There was no significant change of IL-17A concentration before and after radiotherapy in radiation pneumonitis group, but after radiotherapy IL-17A concentration in serum were remarkably higher than that in non-radiation pneumonitis group (P<0.05). Correlation analysis found that the change of ICAM-1 before and after radiotherapy has no obvious correlation with the incidence of radiation pneumonitis, and IL-17A change has obvious correlation with the incidence of radiation pneumonitis. CONCLUSIONS: On the basis of strictly controlling radiation dose on normal tissue, IL-17A in serum could be the predictive factors of radiation pneumonitis for local advanced NSCLC patients with concurrent chemoradiotherapy.

MiR-135a-5p represses proliferation of HNSCC by targeting HOXA10.

Objectives: This research aimed to explore the role of miR-135a-5p in head and neck squamous cell carcinoma (HNSCC) cells and its influence on cell viability. Moreover, we aimed to compare effects of miR-135a-5p and miR-494 in HNSCC, which was found to repress HOXA10 expression in oral cancer. Methods: The association between miR-135a-5p and HOXA10 was confirmed by green fluorescence protein reporter assay and qRT-PCR. The expression levels of HOXA10 in HNSCC cell lines (CAL-27, FaDu and NEC) were examined using western blot. The expression levels of HOXA10 in FaDu cells and CAL-27 cells were examined by western blot after transfection with miR-135a-5p mimics and miR-494 mimics. Colony formation assay and flow cytometry assay were respectively utilized to detect the proliferation and apoptosis of HNSCC cells after transfection with HOXA10 plasmids and HOXA10-KO plasmids. In vitro tumor xenograft experiments were performed to analyze the inhibitive effect of miR-135a-5p on HOXA10 in BALA/c mice. Results: HOXA10 was overexpressed in HNSCC cells, while miR-135a-5p was under-expressed. Therefore, low expression of HOXA10 lengthened disease-free survival time and overall survival time. MiR-135a-5p overexpression could inhibit HOXA10 expression by directly targeting HOXA10 3'UTR, and the inhibition was more effective than miR-494. HOXA10 suppression inhibited proliferation and enhanced apoptosis of HNSCC cells. In vivo experiments showed that miR-135a-5p could decelerate the growth of tumor cells in mice by downregulating HOXA10 expression. Conclusion: MiR-135a-5p could repress HNSCC cells proliferation and enhance apoptosis by directly targeting HOXA10, implying miR-135a-5p's significance on HNSCC treatment.